The pathogenesis of the uremic manifestations is not known and has been attributed to uremic toxins. Many toxins have been implicated but none has been definitely proven to cause some or all of the uremic abnormalities. We have accumulated evidence during the last 10 years indicating that the excess levels of parathyroid hormone (PTH) in the blood of the uremic patients may play an important role in the genesis of the uremic syndrome and that PTH may be a major uremic toxin. The specific aims of our research are to: 1. Examine the effects of PTH on in vitro systems to understand the mechanisms of action of the hormone on various organs and to explore whether such effects have relevance to any of the uremic manifestations. 2. Investigate the role of excess PTH in the genesis of the various components of the uremic syndrome in experimental animals with chronic renal failure and examine, whenever feasible, the effects of PTH on the function of various organs in animals with normal renal function. 3. Evaluate in renal failure patients the consequences of reduction of levels of PTH or of the blocking of action of PTH on the various signs and symptoms of uremia. Our proposed research not only attempts to document a uremic toxin, but also to identify a toxin (PTH) whose source could be controlled, allowing us to prevent its accumulation and to reduce its levels if they are already elevated; or whose actions on cells could be blocked. Thus, our results may have tremendous clinical implications. They may provide rational approaches to ameliorate or prevent many of the components of the uremic syndrome.